Systemic morphine administered via patient controlled analgesia (PCA) pumps and oral narcotics are the leading drugs used to treat post-operative pain. These drugs are very effective but have significant side effects, including respiratory depression, nausea, ileus, and a potential for addiction. Due to the addiction potential, these medications are often under-prescribed so that patients continue to experience moderate to severe pain in the immediate post-operative period. Local anesthetics can be used to avoid these side effects. However, the available drugs are very short acting with a maximum of six to eight hours of pain relief. Post-operative pain typically lasts more than two days. A long-acting local anesthetic that could safely release pain medication over two to four days that truly relieve pain without systemic side effects would potentially provide a significant advantage over the leading drugs used to treat post-operative pain.
Much effort has been made to develop sustained or controlled release local anesthetic drug products. These products may be achieved by microencapsulation such as microspheres, microparticles, and implants. The drug delivery vehicle typically consists of a polymeric matrix from which drug is released by diffusion and/or degradation of the matrix.
U.S. Pat. Nos. 6,214,387, 6,921,541, 6,521,259 and 8,221,778 describe preparation and testing of many polymers, such as polyanhydrides, polylactic acid-glycolic acid copolymers and polyorthoesters used as bioerodible matrices for the controlled release of local anesthetics. The active ingredient, a local anesthetic, is typically entrapped or encapsulated in microspheres or microparticles which are then introduced into the surgical cavity via injection, infusion or in the form of implant.
For application such as treatment of post-operative pain, analgesic activity of only a few days would be desirable. Because erosion of poly(DL-lactic acid) is measured in months, and even years, and the erosion time of poly(lactide-co-glycolide) copolymers is measured in weeks to months, these erosion times are clearly not optimal for short term therapy. In addition, the degradation products of these polymers are glycolic acids and lactic acids, which are very acidic and could cause inflammation.
Kim et al., U.S. Pat. No. 8,182,835 describes encapsulating local anesthetics in liposomes, such as multivesicular liposomes, with high encapsulation efficiency and slow drug release in vivo. Liposomal bupivacaine formulations were also investigated, but in vitro releases of less than twelve hours were achieved. Commercial products (e.g., EXPAREL®) were found to reduce mean pain intensity only during the first 24 hours following study drug administration. U.S. Pat. No. 7,053,209 describes a high viscosity liquid controlled delivery system using nonpolymeric esters or mixed esters of one or more carboxylic acids suitable for the delivery of active substances in a controlled fashion. Unfortunately, this system was not able to properly control release bupivacaine, and the drug product based on it only showed pain-relief comparable to the bupivacaine HCl solution commercial product in a phase II trial.
U.S. Pat. Nos. 6,613,355, 6,790,458 and 6,861,068 describes a semi-solid delivery vehicle contains a polyorthoester and an excipient to control release the active ingredients. A long-acting mepivacaine was developed using this semi-solid drug delivery technology. Unfortunately, only about 3 wt % of mepivacaine is able to be loaded into the polyorthoester vehicle due to the drug's low solubility in the vehicle (Barr et al., 2002, Adv Drug Del Rev 54:1041-48). Further, the controlled release of mepivacaine was only extended from two hours to about six hours in rat animal model studies. This drug product showed comparable pain-relief to the bupivacaine HCl solution commercial product in a phase II trial.
While the above systems are useful, their manufacture processes are complicated, cumbersome and expensive. In addition, they are often associated with an initial higher release of drug immediately after injection (also called “burst”) followed by inconsistent and poor drug release kinetics, thus lack of reliability in pain relief in animal studies and human trials. There remains a need for controlled release of drugs suitable for pain management.